The objective of this program is to develop a therapeutic which can prevent acute inflammation from destroying living tissue in proximity to a severe burn injury. This drug would reduce the severity of burn injuries by reducing the need for skin grafting and other surgical procedures and decreasing the time required for the wound to heal. This project is based on the finding that natural antibodies play a key role in the initiation of the inflammatory response at the site of tissue injury. Initial studies demonstrated that the acute inflammatory response could be blocked by certain peptides which prevented the binding of natural antibodies to specific antigens at the site of injury. The Phase I project goal was to determine if this mechanism could be applied to burn injury and if these peptides were effective in controlling inflammation following burn injury in mice. The Phase I project was highly successful. All of the aims were achieved and additional data were obtained in both mouse and rat models to support the probability of success of this model in the treatment of acute burn injury. The Phase II project is focused on generating the pre-clinical data that will support the movement of this drug candidate into human trials. Specifically the aims are targeted at 1) determining the optimal formulation, dose, route and timing of delivery of therapy for the treatment of clinical burns, 2) determining the distribution, degradation and toxicity of the selected drug candidate, and 3) determining the effectiveness of the proposed drug in a pig model of burn injury. Pigs are accepted as an animal model with skin structure similar to humans and will add to the data supporting the cross species effectiveness obtained in mice and rats. This approach, if successful, would be a breakthrough in the treatment of severe burns. PUBLIC HEALTH RELEVANCE: Over 75,000 patients per year are hospitalized for severe burn injuries, spending an average of two weeks undergoing painful and expensive treatments for their injuries, including antibiotics, nutritional and surgical care of the wound. Much of the final extent of tissue loss following burn injury is not from the burn itself, but from the acute inflammatory reaction which occurs at the site of the injury and the surrounding tissue. The goal of this project is to develop therapeutic agents which reduce the acute inflammatory destruction of living tissue surrounding a burn wound and result in a wound which heals faster and with less need for skin grafting or other surgical intervention, reduced hospitalization costs and less permanent scarring and debilitating effects to the patient.